Short Introduction to the USP 4 Method

USP <2040>: New Regulations for Nutraceutical
Testing using Established Testing Techniques
21 October 2011 – Toronto, Canada
Geoffrey Grove, Product Manager, Business Unit America
Agenda
 USP
 Relation to the FDA and to the pharmaceutical and
nutraceutical industry
 Hierarchy of the USP regulations
 Regulations regarding dissolution
 Disintegration <2040>, <701>
 Apparatus types
 Procedures
 Acceptance Criteria
 Dissolution <2040>, <711>
 Apparatus types
 Procedures
 Acceptance Criteria
The USP and the FDA
 Publishes
 Best Practices and
procedures
 Apparatus Specifications
 Monographs
 Strength, purity, quality,
packaging and labeling
 Enforcement
 Best Practices
 Inspects labs, and
manufacturing
facilities/processes
 Produces the USP PVT
calibration standards
 Approval
 Safety and Efficacy
 Marketing
 …More
 “Compendial”, refers to items
listed in the USP
 Developed a mechanical
calibration with ASTM
Dissolution in USP Monographs
Compendial Dissolution is over forty years old…
 1970:
6 monographs
 1975:
12 monographs
 1980:
60 monographs
 1990:
462 monographs
 2000:
550 monographs
 2005:
647 monographs (584 Dissolution + 63 Drug Release)
 2010:
750 monographs (741 Dissolution + 9 Drug Release)
 Hierarchy: General Notices are trumped by General Chapters
which are trumped by Monographs
<2040> Disintegration
 If there is no monograph, you cannot legally make a label claim
that a product is in “compliance” with the USP.
 The USP encourages monographs submissions from the industry.
 Troches, chewables and extended release formulations are
excluded from disintegration testing, but have other requirements.
 If a dosage form has physical dimensions less than or equal to
18 mm in the largest dimension, then Apparatus “A” is used.
Otherwise, use Apparatus “B”.
<2040> Revision Bulletin
 In addition the published
USP, also be aware of
“Revision Bulletins”,
which give guidance
regarding coming
changes.
 In December of this
year, <2040> will begin
to require Apparatus 4
for dissolution, replacing
the current
disintegration test.
<701> Disintegration: Instrumentation
 Multiple vendors
 Instrumentation is not specified
in the USP
 “Apparatus” refers to the basket
design, motion of the basket,
and the temperature
<701> Disintegration: Apparatus types
Apparatus A
Apparatus B
<2040> Disintegration Procedures
Uncoated Tablet
Sublingual Tablets
Buccal Tablet
Hard Shell Capsule
Plain coated Tablet
Delayed Release
(Enteric Coated)
Tablets
Delayed Release
(Enteric Coated)
Softshell capsules
Time (min)
30
30
If Sugar Coated
Media
Water or see monograph
Water or see monograph
Disk
240
Water or see monograph
see monograph
0.05M Acetate Buffer pH 4.5
30
5 min. in 25
Water or see monograph
degree C water
60
5 min. in 25
degree C water
Need upper mesh
Simulated Gastric TS
see monograph
Simulated Intestinal Fluid TS
60
Simulated Gastric TS
60
Notes
No Disk
Mentions the use of
Apparatus B
Simulated Intestinal Fluid TS With Disk
 Acceptance Criteria: If 1-2 fail, then run 12 more, if 3 out of 18 fail, then the test
fails.
 Use of Disks (by default): Vitamin-mineral (yes), botanical and dietary
supplements other than vitamin- mineral, and enteric coated (no).
The USP Dissolution Apparatus Types
 USP 29 - NF 24 <711> Dissolution






Apparatus 1–Basket Apparatus
Apparatus 2–Paddle Apparatus
Apparatus 3–Reciprocating Cylinder (not JP)
Apparatus 4–Flow-through Cell Apparatus (JP - App.3)
Apparatus 5, 6 – Paddle over disk, rotating cylinder
Apparatus 7 – Reciprocating Holder
 Ph. Eur. 2.9.3 Dissolution Test for Solid Dosage Forms
 JP General Tests - Processes and Apparatus 6.10 Dissolution Test
<711> Dissolution: Apparatus types
Apparatus 1 and 2
<711> Dissolution: Apparatus types
Apparatus 1 and 2
<711> Dissolution: Apparatus types
Apparatus 3
<701> Disintegration: Apparatus types
Apparatus 4
Dissolution Requirements
 Vitamin A (if
present) – for
tablets only
Dissolution Requirements
 Vitamin A: App 2 with actinic vessels
 Folic Acid:
 Test 1
 App 1: capsules
 App 2: tablets
 Test 2:
 App 3
 Note: …and you still need to do the index vitamin and/or
mineral testing
Dissolution Requirements
 Dissolution conditions for index water soluble vitamins and index
minerals:
 Test 1:
 App 1: capsules
 App 2: tablets
 Test 2: (not for minerals)
 Apparatus 3
 Note: You must still test for Folic acid if present.
 Rupture Test for soft shell capsules:
 Now App 4 lipidic cell application
Questions?
Instrument development...
19
Semi-automated closed-loop system
In the lab…
21
The Flow Cell
 The test sample is
located in a small-volume
cell through which solvent
passes at 37 °C.
 The eluate is filtered upon
leaving the cell.
 The eluate is analyzed
directly (on-line) with a
spectrophotometer and/or
collected in a fraction
collector (off-line).
Open and Closed Loop Configurations
 Open System – uses, continuously, fresh media
pumped through the cell. A known part of the eluate is
analyzed and the rest of the flow goes to waste. Very
easy pH change possible
 Closed Loop System – after the cell the media is
returned and then re-circulated for each cell
Open loop Off-line : flow direction
Fraction collector can be replaced by a UV-Vis to
have an Open loop On-line with a splitting valve
When do we use an Open Loop System?
 For poorly soluble compounds, low dosage forms to
maintain the sink conditions
 Easy pH change for pH sensitive release products
 IVIVC studies that require multiple pH changes
 Any method that requires an automated media change
Closed loop On-line: flow direction
When do we use a Closed Loop System?
 Need to work with any fixed volume, less than 400 mL
or more than 1000 ml of media. An official USP method
for small volume (as low as 5 mL depending on the
cell)
 Low amount of drug to detect
 Dissolution of unique dosage forms (powders, pellets,
suspensions, suppositories, soft gelatin capsules,
implants, drug-eluting stents, microspheres, gels and
creams…).
 Solves product build up, sticking, floating, sampling
problems of paddle method
USP chapter 711
European Pharmacopeia
USP 4 flow cells
Questions?